Sepsis is a life-threatening disorder caused by infection that leads to systemic inflammation, shock and organ failure. It constitutes the tenth leading cause of death in the United States and represents a major health challenge. With modern medical management most patients survive the initial onset of sepsis. Unfortunately, many go on to develop organ failure despite current therapies, the extent of which determines their risk of death, and also their risk of prolonged functional impairment should they survive. As such, there is a clear need for better strategies to limit organ failure in sepsis patients. The reason sepsis leads to organ failure is because, during this disease, the cells that make up vital organs accumulate damage to their proteins and organelles, undermining their function and also promoting cell death. We hypothesize that part of the reason that cells accumulate damaged components during sepsis is because a key housekeeping pathway called macroautophagy becomes inhibited, and that this inhibition is related to a loss of circadian rhythms during sepsis Macroautophagy is a catabolic process by which cells cannibalize components of their cytoplasm in order to survive starvation conditions and to recycle damaged organelles. To investigate our hypothesis, we propose to investigate the regulation and physiologic function of macroautophagy in mouse models of sepsis and also in human disease. Specifically the aims of our project are: 1) To examine the regulation and significance of macroautophagy in the mouse cecal ligation and puncture (CLP) model of sepsis. 2) To determine the molecular link between macroautophagy disruption and circadian clock disruption during experimental sepsis. 3) To examine the regulation of macroautophagy in human sepsis. This project will contribute to a better understanding of organ failure during sepsis, which is a major contributor to the morbidity of this disorder. It will clarify the significance of macroautophagy inhibition during sepsis in boh experimental animals and patients. Such information may inform the rational design of macroautophagy- based interventions that mitigate organ failure in sepsis patients and lead to improved clinical outcomes. PUBLIC HEALTH RELEVANCE: The proposed project will improve our understanding of sepsis, which is a major health issue in the United States. It will define how an adaptive mechanism called macroautophagy is affected during septic illness, and how it contributes to the severity and outcome of this important disease. The information our project produces will serve an important public health need, as it will be used to develop new ways of treating sepsis by stimulating macroautophagy, thereby limiting organ damage and improving survival.